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Cardiovascular Aging

Increased mitochondrial H₂O₂ production promotes endothelial NF-B activation in aged rat arteries

Department of Physiology, New York Medical College, Valhalla, New York

Submitted 10 December 2006 ; accepted in final form 8 March 2007

Previous studies have shown that the aging vascular system undergoes pro-atherogenic phenotypic changes, including increased oxidative stress and a pro-inflammatory shift in endothelial gene expression profile. To elucidate the link between increased oxidative stress and vascular inflammation in aging, we compared the carotid arteries and aortas of young and aged (24 mo old) Fisher 344 rats. In aged vessels there was an increased NF-B activity (assessed by luciferase reporter gene assay and NF-B binding assay), which was attenuated by scavenging H₂O₂. Aging did not alter the vascular mRNA and protein expression of p65 and p50 subunits of NF-B. In endothelial cells of aged vessels there was an increased production of H₂O₂ (assessed by 5,6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate-acetyl ester fluorescence), which was attenuated by the mitochondrial uncoupler FCCP. In young arteries and cultured endothelial cells, antimycin A plus succinate significantly increased FCCP-sensitive mitochondrial H₂O₂ generation, which was associated with activation of NF-B. In aged vessels inhibition of NF-B (by pyrrolidenedithiocarbamate, resveratrol) significantly attenuated inflammatory gene expression and inhibited monocyte adhesiveness. Thus increased mitochondrial oxidative stress contributes to endothelial NF-B activation, which contributes to the pro-inflammatory phenotypic alterations in the aged vaculature. Our model predicts that by reducing mitochondrial H₂O₂ production and/or directly inhibiting NF-B novel anti-aging pharmacological treatments (e.g., calorie restriction mimetics) will exert significant anti-inflammatory and vasoprotective effects.

inflammation; endothelial cell; senescence; aging; resveratrol

This article has been cited by other articles:

				A. Csiszar, N. Labinskyy, A. Podlutsky, P. M. Kaminski, M. S. Wolin, C. Zhang, P. Mukhopadhyay, P. Pacher, F. Hu, R. de Cabo, et al. Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2721 - H2735. [Abstract] [Full Text] [PDF]

				Z. Ungvari, N. Labinskyy, S. Gupte, P. N. Chander, J. G. Edwards, and A. Csiszar Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2121 - H2128. [Abstract] [Full Text] [PDF]

				Z. Ungvari, C. Parrado-Fernandez, A. Csiszar, and R. de Cabo Mechanisms Underlying Caloric Restriction and Lifespan Regulation: Implications for Vascular Aging Circ. Res., March 14, 2008; 102(5): 519 - 528. [Abstract] [Full Text] [PDF]